The TSC1-2 tumor suppressor controls insulin-PI3K signaling via regulation of IRS proteins

Laura S. Harrington; Greg M. Findlay; Alex Gray; Tatiana Tolkacheva; Simon Wigfield; Heike Rebholz; Jill Barnett; Nick R. Leslie; Susan Cheng; Peter R. Shepherd; Ivan Gout; C. Peter Downes; Richard F. Lamb

doi:10.1083/jcb.200403069

The TSC1-2 tumor suppressor controls insulin-PI3K signaling via regulation of IRS proteins

Laura S. Harrington, Greg M. Findlay, Alex Gray, Tatiana Tolkacheva, Simon Wigfield, Heike Rebholz, Jill Barnett, Nick R. Leslie, Susan Cheng, Peter R. Shepherd, Ivan Gout, C. Peter Downes, Richard F. Lamb

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Abstract

Insulin-like growth factors elicit many responses through activation of phosphoinositide 3-OH kinase (PI3K). The tuberous sclerosis complex (TSC1-2) suppresses cell growth by negatively regulating a protein kinase, p70S6K (S6K1), which generally requires PI3K signals for its activation. Here, we show that TSC1-2 is required for insulin signaling to PI3K. TSC1-2 maintains insulin signaling to PI3K by restraining the activity of S6K, which when activated inactivates insulin receptor substrate (IRS) function, via repression of IRS-1 gene expression and via direct phosphorylation of IRS-1. Our results argue that the low malignant potential of tumors arising from TSC1-2 dysfunction may be explained by the failure of TSC mutant cells to activate PI3K and its downstream effectors.

Original language	English
Pages (from-to)	213-223
Number of pages	11
Journal	Journal of Cell Biology
Volume	166
Issue number	2
DOIs	https://doi.org/10.1083/jcb.200403069
Publication status	Published - 19 Jul 2004

Keywords

6K
Nsulin
PI3K
RS proteins
TSC1-2

ASJC Scopus subject areas

Cell Biology

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10.1083/jcb.200403069

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title = "The TSC1-2 tumor suppressor controls insulin-PI3K signaling via regulation of IRS proteins",

abstract = "Insulin-like growth factors elicit many responses through activation of phosphoinositide 3-OH kinase (PI3K). The tuberous sclerosis complex (TSC1-2) suppresses cell growth by negatively regulating a protein kinase, p70S6K (S6K1), which generally requires PI3K signals for its activation. Here, we show that TSC1-2 is required for insulin signaling to PI3K. TSC1-2 maintains insulin signaling to PI3K by restraining the activity of S6K, which when activated inactivates insulin receptor substrate (IRS) function, via repression of IRS-1 gene expression and via direct phosphorylation of IRS-1. Our results argue that the low malignant potential of tumors arising from TSC1-2 dysfunction may be explained by the failure of TSC mutant cells to activate PI3K and its downstream effectors.",

keywords = "6K, Nsulin, PI3K, RS proteins, TSC1-2",

author = "Harrington, {Laura S.} and Findlay, {Greg M.} and Alex Gray and Tatiana Tolkacheva and Simon Wigfield and Heike Rebholz and Jill Barnett and Leslie, {Nick R.} and Susan Cheng and Shepherd, {Peter R.} and Ivan Gout and Downes, {C. Peter} and Lamb, {Richard F.}",

year = "2004",

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AU - Harrington, Laura S.

AU - Findlay, Greg M.

AU - Gray, Alex

AU - Tolkacheva, Tatiana

AU - Wigfield, Simon

AU - Rebholz, Heike

AU - Barnett, Jill

AU - Leslie, Nick R.

AU - Cheng, Susan

AU - Shepherd, Peter R.

AU - Gout, Ivan

AU - Downes, C. Peter

AU - Lamb, Richard F.

PY - 2004/7/19

Y1 - 2004/7/19

N2 - Insulin-like growth factors elicit many responses through activation of phosphoinositide 3-OH kinase (PI3K). The tuberous sclerosis complex (TSC1-2) suppresses cell growth by negatively regulating a protein kinase, p70S6K (S6K1), which generally requires PI3K signals for its activation. Here, we show that TSC1-2 is required for insulin signaling to PI3K. TSC1-2 maintains insulin signaling to PI3K by restraining the activity of S6K, which when activated inactivates insulin receptor substrate (IRS) function, via repression of IRS-1 gene expression and via direct phosphorylation of IRS-1. Our results argue that the low malignant potential of tumors arising from TSC1-2 dysfunction may be explained by the failure of TSC mutant cells to activate PI3K and its downstream effectors.

AB - Insulin-like growth factors elicit many responses through activation of phosphoinositide 3-OH kinase (PI3K). The tuberous sclerosis complex (TSC1-2) suppresses cell growth by negatively regulating a protein kinase, p70S6K (S6K1), which generally requires PI3K signals for its activation. Here, we show that TSC1-2 is required for insulin signaling to PI3K. TSC1-2 maintains insulin signaling to PI3K by restraining the activity of S6K, which when activated inactivates insulin receptor substrate (IRS) function, via repression of IRS-1 gene expression and via direct phosphorylation of IRS-1. Our results argue that the low malignant potential of tumors arising from TSC1-2 dysfunction may be explained by the failure of TSC mutant cells to activate PI3K and its downstream effectors.

KW - 6K

KW - Nsulin

KW - PI3K

KW - RS proteins

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JO - Journal of Cell Biology

JF - Journal of Cell Biology

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ER -

The TSC1-2 tumor suppressor controls insulin-PI3K signaling via regulation of IRS proteins

Abstract

Keywords

ASJC Scopus subject areas

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